The essential fatty acids and their conversions in the body are shown in the following table.
n-6 EFAs n-3 EFAs 18:2n-6 18:3n-3 Linoleic acid (LA) .alpha.-Linolenic acid (ALA) .arrow-down dbl. .delta.-6-desacurase .arrow-down dbl. 18:3n-6 18:4n-3 y-Linolenic acid (GLA) Stearidonic acid (SA) .arrow-down dbl. elongation .arrow-down dbl. 20:3n-6 20:4n-3 Dihomo-.gamma.-linolenic acid Eicosatetraenoic acid (DGLA) .arrow-down dbl. .delta.-5-desacurase .arrow-down dbl. 20:4n-6 20:5n-3 Arachidonic acid (AA) Eicosapentaenoic acid (EPA) .arrow-down dbl. elongation .arrow-down dbl. 22:4n-6 22:5n-3 Adrenic acid (AdrA) .arrow-down dbl. .delta.-4-desacurase .arrow-down dbl. 22:5n-6 22-6n-3 Docosahexaenoic acid (DHA)
The acids, which in nature are of the all -cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g.LA z,z-octadeca-9,12-dienoic acid or DHA z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturazion and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as, correspondingly, 18:2 n-6 or 22:6 n-3, are convenient. Initials, e.g. EPA, and shortened forms of the name e.g. eicosaerntaenoic acid, are used as trivial names in some instances.
In previous patent applications EPA-0347056 and EPA-0599576 we have drawn attention to the action of various essential fatty acids in schizophrenia and have claimed the use of these fatty acids in treatment. We have particularly drawn attention to the low red cell levels of arachidonic acid (AA) and docosahexaenoic acid (DHA) and to the use of these fatty acids.
Present Work
We have now unexpectedly found that one Particular essential fatty acid which was previously accorded only a minor role is in fact particularly effective in treatment. This is eicosapentaenoic acid (EPA; 20:5n-3) which is present in the brain in only small amounts compared to AA and DHA. However, in a trial of treatment we have found that EPA is exceptionally effective in treatment of schizophrenia. Particularly effective are preparations comprising EPA in amounts of more than 20% of the total fatty acids present (preferably the total unsaturated fatty acids present), preferably more than 40% and very preferably more than 70%.
Studies of the use of omega-3 essential fatty acids in treatment, using a mixture of DHA and EPA, have previously shown modestly beneficial effects (Mellor et at, Human Psychopharmacology 11:39-46, 1996). The preparation used contained 18% of EPA and 12% of DHA and so far as this disclosure goes the therapeutic effects could have been caused by either component or both. An analysis of the relationship between fatty acid change and schizophrenia symptoms showed that a rise in the total omega-3 content of red cell membranes was associated with a fall in schizophrenic symptoms.
We therefore decided to try to determine the relative importance of EPA and DHA in schizophrenia. A study was carried out with 30 schizophrenia patients, most of whom had both positive and negative symptoms as shown by the positive and negative symptom scale (PANSS) and also had some evidence of tardive dyskinesia as shown by the abnormal involuntary movements scale (AIMS). Patients were randomly assigned on a double blind basis to treatment with 20 ml of a placebo emulsion, 20 ml of a 40% emulsion providing 8 g of oil containing approximately 2.0 g of EPA and 0.4 g of DHA per day (`EPA group`), and 20 ml of an emulsion providing approximately 2.3 g of DHA and 0.5 g of EPA per day (`DHA group`) in 8 g of oil. Patients were scored at baseline and at the end of 12 weeks of treatment. In the placebo group, 9 patients were unchanged or deteriorated on the PANSS and AIMS scores and one improved. In the DHA group, seven patients were unchanged or deteriorated and three patients improved. In contrast, in the EPA group one patient was unchanged but nine patients showed improvement. The improvement was seen in both the negative and positive symptom scores and in the AIMS score. There was therefore a broad spectrum improvement in all aspects of the schizophrenia syndrome. The DHA group was not significantly different from placebo whereas the EPA group was significantly better than both the DHA group and the placebo group (p&lt;0.02 in both cases).
It is therefore possible to conclude that the main therapeutic effect of treatment with EFAs is attributable to the effect of EPA. The other EFAs may contribute to some degree but there can be no doubt that EPA is primarily responsible for the positive effects of treatment with omega-3 EFA preparations. We concluded that EPA should also be effective in other psychiatric disorders such as Alzheimer's disease and depression since low levels of n-3 fatty acids have been shown in the blood and/or the brain of patients with these disorders also Two patients with severe depression not responsive to the usual anti-depressants were therefore treated with the EPA formulation as used in the schizophrenia trial. Within 4 weeks both had shown remarkable improvement in their symptoms.
While we cannot be certain of the mechanism by which EPA is working, one possibility is that it is inhibiting the enzyme, phospholipase A2. There is considerable evidence that phospholipase (PL) A2 activity is elevated in schizophrenia (Horrobin et al, Schizophrenia Research 1994; 13: 195-207). Compounds which safely inhibit PLA2 might therefore be expected to have a therapeutic effect. In in vitro studies of the effects of fatty acids on PLA2 activity we have found that EPA is a potent inhibitor, whereas the relatively similar fatty acid, DHA is not. This might explain why DHA did not prove effective in the clinical studies.
We have further found that another n-3 fatty acid, stearidonic acid (18:4 n-3), is as effective in inhibiting, PLA2 as is EPA. EPA and SA are 20- and 18-carbon fatty acids which have in fact been shown to inhibit the activity of phospholipase A.sub.2 (Finnen, Biochem Soc. Trans 1991; 19:915). In contrast, DHA is A 22-carbon fatty acid which like other 22-carbon acids does not inhibit phospholipase. This may offer an explanation for the differences between EPA and DHA since there is evidence for overactivity of phospholipase A.sub.2 in schizophrenia. We therefore propose that stearidonic acid will be effective in treating schizophrenia and the other disorders and we include its use for that purpose alone or with EPA.
The n-6 EFAs such as linoleic acid, gamnmalinolenic acid (GLA) dihomogammalinolenic acid (DGLA) and arachidonic acid (AA) are important in brain structure. GLA can be metabolised to DGLA and AA. We therefore tried to see whether the addition of an oil containing linoleic acid and GLA would be beneficial in two individuals who had responded to EPA. In fact their condition appeared to be less good with addition of the n-6 EFAs. It is therefore better to treat with EPA preparations in which the levels of n-6 EFAs are kept at a low level compared to the concentration of EPA. Either n-6 EFAs should be absent or if present at a ratio to EPA of not more than 1:3, preferably 1:4 or less.
In any case to ensure that the effects secured are not countered the weight ratio of SA/EPA to any DHA present is desirably not less than 3:1 by weight and desirably 4:1 or more.